Using autologous mesenchymal stem cells to treat multiple system atrophy

ABSTRACT

This document provides methods and materials for treating multiple system atrophy in a mammal. Specifically, the methods comprises intrathecally administering to the mammal a composition comprising autologous mesenchymal stem cells (e.g. adipose deprived mesenchymal stem cells) to treat multiple system atrophy. Further disclosed is the composition comprising from about 5×10(6) to about 5×10(8) autologous mesenchymal stem cells.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. § 371of International Application No. PCT/US2016/037632, having anInternational Filing Date of Jun. 15, 2016, which claims priority toU.S. Application Ser. No. 62/175,628, filed on Jun. 15, 2015. Thedisclosure of the prior application are considered part of thedisclosure of this application, and are incorporated in its entiretyinto this application.

BACKGROUND 1. Technical Field

This document relates to methods and materials for treating multiplesystem atrophy. For example, this document provides methods andmaterials for intrathecally administering autologous mesenchymal stemcells (e.g., adipose derived mesenchymal stem cells) to mammals (e.g.,humans) to treat multiple system atrophy.

2. Background Information

Multiple system atrophy is a sporadic and fatal multi-system progressivedisorder characterized by progressive autonomic failure, orthostatichypotension, neurogenic bladder/erectile dysfunction, cerebellar ataxia,corticospinal dysfunction, and Parkinsonism. Multiple system atrophyprogresses relentlessly and survival from diagnosis to death is 2-4years. Multiple system atrophy is a rare disease with a prevalence of3-5 per 100,000. The prevalence is 28/100,000 in persons over the age of65.

SUMMARY

This document provides methods and materials for treating multiplesystem atrophy. For example, this document provides methods andmaterials for using autologous mesenchymal stem cells (e.g., adiposederived mesenchymal stem cells) to treat multiple system atrophy.

As described herein, autologous adipose derived mesenchymal stem cellscan be safely administered intrathecally to humans suffering frommultiple system atrophy to improve one or more symptoms of multiplesystem atrophy and/or to slow the progression of multiple systematrophy.

In general, one aspect of this document features a method of treating amammal having multiple system atrophy. The method comprises, or consistessentially of, intrathecally administering, to the mammal, acomposition comprising autologous mesenchymal stem cells. The mammal canbe a human. The composition can comprise from about 5×10⁶ to about 5×10⁸autologous mesenchymal stem cells. The rate of progression of themultiple system atrophy can be reduced following the administering step.The autologous mesenchymal stem cells can be adipose derived mesenchymalstem cells or bone marrow derived mesenchymal stem cells. The method cancomprise intrathecally administering the composition comprisingautologous mesenchymal stem cells more than one time to the mammal. Themethod can comprise intrathecally administering the compositioncomprising autologous mesenchymal stem cells to the mammal two to tentimes.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a patient treatment protocol.

FIG. 2 is a test schedule table.

FIG. 3 is contains graphs plotting UMSARS I progression in historicalcontrols versus patients who received an intrathecal administration ofautologous mesenchymal stem cells. The left panel shows the projectedUMSARS I change per month by group, while the right panel shows thechange of UMSARS I over time in individual patients following injectionof autologous mesenchymal stem cells (thin solid lines—low dose groupgrey, middle dose group black) versus the expected change (thick dashedline).

FIG. 4 is a graph plotting the results of an RNA-seq analysis, which wasperformed for seven different adipose derived mesenchymal stem celllines and eight different bone marrow derived mesenchymal stem cells.All cell lines were evaluated at confluence. A fold change comparisonfor all genes expressed at greater than 1 reads per kilobase per million(RPKM) was made. Top 50 genes enriched in adipose derived mesenchymalstem cells are listed.

FIG. 5 contains graphs of UMSARS total progression in historicalcontrols and patients who received intrathecal administration ofautologous mesenchymal stem cells (group 1=10 million cells; group 2=50million cells given twice). The top panel shows the change in UMSARStotal as mean and standard deviation for each group. The bottom panelsshow the individual change of UMSARS total over time for patients ingroup 1 (bottom; left) and group 2 (bottom; right) compared to theaverage change seen in historical controls (thick line). Note than allpatients treated with autologous mesenchymal stem cells exhibited slowerdisease progression than the average of the control group. Some patientsexperienced no progression or even improvement at the 6 and 12 monthfollow-up evaluations.

DETAILED DESCRIPTION

This document provides methods and materials for treating multiplesystem atrophy. For example, this document provides methods andmaterials for using autologous mesenchymal stem cells to treat multiplesystem atrophy. As described herein, mesenchymal stem cells can beadministered intrathecally to a mammal suffering from multiple systematrophy to improve one or more symptoms of multiple system atrophyand/or to slow the progression of multiple system atrophy. Examples ofmesenchymal stem cells that can be administered intrathecally to treatmultiple system atrophy include, without limitation, autologous adiposederived mesenchymal stem cells and autologous bone marrow derivedmesenchymal stem cells.

In some cases, adipose derived mesenchymal stem cells expressing thegenes listed in FIG. 4 or having expression levels within the rangeshown for AMSC1-7 in FIG. 4 can be administered intrathecally to amammal suffering from multiple system atrophy to improve one or moresymptoms of multiple system atrophy and/or to slow the progression ofmultiple system atrophy.

In some cases, multiple system atrophy can be treated by administering(e.g., via intrathecal administration) an effective amount of acomposition that includes autologous mesenchymal stem cells (e.g.,adipose derived mesenchymal stem cells). Effective amounts of acomposition containing autologous mesenchymal stem cells (e.g., adiposederived mesenchymal stem cells) can be determined by a physician, takinginto account various factors such as overall health status, body weight,sex, diet, time and route of administration, other medications, and anyother relevant clinical factors. As used herein, an “effective amount”or “therapeutically effective amount” of a composition is the amountthat is sufficient to provide a beneficial effect to the subject towhich the composition or preparations are delivered. The effectiveamount can be the amount effective to achieve an improved survival rate,a more rapid recovery, an improvement in the quality of life, or animprovement or elimination of one or more symptoms associated with asubject's multiple system atrophy.

In some cases, a composition containing from about 5×10⁶ to about 5×10⁸autologous mesenchymal stem cells (e.g., adipose derived mesenchymalstem cells) can be administered intrathecally to a mammal to treatmultiple system atrophy. For example, about 5×10⁷ (±about 20%)autologous mesenchymal stem cells (e.g., adipose derived mesenchymalstem cells) can be administered intrathecally to a mammal to treatmultiple system atrophy. In some cases, multiple (e.g., two, three,four, five, or more) treatments of cells can be performed to obtain ormaintain an effect.

Any appropriate method can be used to obtain autologous mesenchymal stemcells (e.g., adipose derived mesenchymal stem cells). For example, thetechniques described elsewhere can be used to obtain autologousmesenchymal stem cells (e.g., adipose derived mesenchymal stem cells).See, e.g., Zuk et al., Tissue Engineering, 7(2):211-228 (2001) andSotiropoulou et al., Stem Cells, 24:462-471 (2006).

In some cases, autologous mesenchymal stem cells can be obtained asfollows. After harvesting adipose tissue, the tissue can be fragmented,cut into small pieces, and washed in PBS. Discolored tissue and excessvasculature can be removed, and the tissue can be diced. The tissue canbe re-suspended in about 0.075% Collagenase (Worthington BiochemicalCorporation) in Hank's buffer and incubated at about 37° C. The tube canbe inverted until the visible evidence of tissue is lost. The tissuedigest can be washed by centrifugation in full media (Advanced MEM lowglucose, 5% human platelet lysate, 2 Units per mL Heparin). In somecases, the cells can be passed through filters (e.g., 70 μm and/or 40 μmfilters) to remove large tissue pieces. The cells can be plated andmaintained at less than 90% confluency and passaged when needed using0.25% Trypsin EDTA. The cells can be expanded to obtain an appropriatenumber, and cryopreserved to complete release testing. In some cases,the cells can be thawed and returned to culture conditions for 3-5 daysprior to collection, washing, and preparation for infusion.

A composition containing autologous mesenchymal stem cells (e.g.,adipose derived mesenchymal stem cells) can be administered one or morethan one time to the same mammal (e.g., human). For example, acomposition containing autologous mesenchymal stem cells (e.g., adiposederived mesenchymal stem cells) can be administered intrathecally to ahuman at least monthly (e.g., about monthly ±4 days) for two to 36months.

Any appropriate mammal can be treated as described herein. For example,humans, non-human primates (e.g., chimpanzees, baboons, or monkeys),horses, dogs, cats, rabbits, mice, or rats can be treated as describedherein.

In some cases, the methods described herein can include monitoringmultiple system atrophy in the mammal to, for example, determine if themultiple system atrophy is improving with treatment. Any appropriatemethod can be used to monitor multiple system atrophy. For example,neurologic examination, MSA rating score (UMSARS), autonomic functiontesting, MRI measurements of the brain, and/or PET/SPECT imaging can beused to monitor the progression of multiple system atrophy.

In some cases, the methods and materials provided herein can be used totreat conditions other than multiple system atrophy. For example, themethods and materials provided herein can be used to treat Parkinson'sdisease, diffuse Lewy-body disease, Lewy-body dementia, pure autonomicfailure, and/or tauopathies such as Alzheimer's disease, frontotemporaldementia, corticobasal degeneration, and progressive supranuclear palsy.In some cases, mesenchymal stem cells can be administered intrathecallyto a mammal suffering from one or more of these other conditions toimprove one or more symptoms of those conditions and/or to slow theprogression of those conditions.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLES Example 1 Intrathecal Administration of Autologous MesenchymalStem Cells

Rabbits were injected with 1×10⁷ autologous mesenchymal stem cells viasingle injections per rabbit or three injections per rabbit over acourse of 12 weeks. Animals were monitored for acute and chronic adverseevents including: subarachnoid irritation, aseptic meningitis with painor seizures, and unregulated growth of cells to form intrathecal tumors.Ratios of the organ to the body weight were measured and calculated foreach rabbit. Macroscopic examination was conducted for each organ.

There were no significant or abnormal findings except in one rabbit thatexhibited a small accumulation of mesenchymal cells in the subarachnoidspace in the region of the injection, and one that exhibited a smallinflammatory cell collection in the extradural space in the region ofthe injection.

Blood test results did not reveal any significant difference betweencontrol and experimental groups after both 4 and 12 weeks. There were nosignificant differences for the organ to body weight ratios betweencontrol and experimental groups. Macroscopic and microscopicexaminations also did not reveal any meaningful difference between thecontrol and experimental groups. Functional assessments did not reveal adifference directly related to the injection of mesenchymal stem cells.

These results demonstrate that mesenchymal stem cells can be safelyinjected into that CSF via, for example, intrathecal administration.

Example 2 Intrathecal Administration of Autologous Mesenchymal StemDells Into a Human

A human patient with amyotrophic lateral sclerosis (ALS) wasadministered 1×10⁶ autologous mesenchymal stem cells. The patienttolerated the procedure well, with stable vital signs and no fevers.Spinal fluid analyses at one and three weeks after mesenchymal stem celladministration were stable when compared to baseline studies. No adverseevents associated with the administered mesenchymal stem cells werenoted.

The patient's ALS progressed at an expected rate, and the patient passedaway from the disease.

Example 3 Intrathecal Administration of Autologous Mesenchymal StemCells to Treat Multiple System Atrophy

Mesenchymal stem cells are isolated from a fat biopsy obtained from ahuman with multiple system atrophy. The mesenchymal stem cells areexpanded and released for human use after meeting release criteria.Briefly, after harvesting, the adipose tissue is fragmented, cut intosmall pieces, and washed in PBS. Discolored tissue and excessvasculature is removed, and the tissue is diced. The tissue isre-suspended in 0.075% Collagenase (Worthington Biochemical Corporation)in Hank's buffer and incubated at 37° C. The tube is inverted until thevisible evidence of tissue is lost. The tissue digest is washed bycentrifugation in full media (Advanced MEM low glucose, 5% humanplatelet lysate, 2 units per mL Heparin). In some cases, the cells arepassed through filters (e.g., 70 μm and 40 μm filters) to remove largetissue pieces. Cells are plated and maintained at less than 90%confluency and are passaged when needed using 0.25% Trypsin EDTA. Cellsare expanded and cryopreserved to complete release testing. In somecases, cells are thawed and returned to culture conditions for 3-5 daysprior to collection, washing, and preparation for infusion.

Once released, the mesenchymal stem cells (e.g., from about 1×10⁷ toabout 1×10⁸ cells) are injected intrathecally into that same human withmultiple system atrophy. In some cases, subsequent intrathecalinjections of from about 1×10⁷ to about 1×10⁸ mesenchymal stem cells areadministered to the human monthly, every other month, every 6 months, orevery year for up to about 3 years.

Example 4 Clinical Study to Evaluate Treating Multiple System Atrophy

Twenty-four adult humans with multiple system atrophy (probable, basedon Gilman criteria) and UMSARS I score ≤17 are selected in order toexclude cases that are very advanced. Briefly, the inclusion criteriaare: (1) participants aged 30-80 years with a diagnosis of multiplesystem atrophy based on clinical criteria and standardized autonomictesting. This approach allows for identification of patients withmultiple system atrophy with very high specificity and is yet sensitiveenough to allow for enrollment of patients at a disease stage at whichan intervention on the natural disease course has a meaningful impact onpatient outcome. Patients therefore are selected to fulfill GilmanCriteria for probable multiple system atrophy of the parkinsoniansubtype (MSA-P) or cerebellar subtype (MSA-C), have an UMSARS I score≤17, and have findings on autonomic function testing suggestive ofmultiple system atrophy (CASS≥5 and/or TST % anhidrosis≥25%); (2)participants who are less than 4 years from the time of documented MSAdiagnosis; (3) participants with an anticipated survival of at least 3years; (4) participants who are willing and able to give informedconsent; and (5) “Normal” cognition as assessed by MMSE. A value >24 isrequired. Any of the following conditions exclude a participant: (1)Pregnant or breastfeeding women, and women of childbearing potential whodo not practice an acceptable method of birth control. Acceptablemethods of birth control in this study are: surgical sterilization,intrauterine devices, partner's vasectomy, a double-protection method(condom or diaphragm with spermicide), hormonal contraceptive drug(i.e., oral contraceptive, contraceptive patch, long-acting injectablecontraceptive) with a required second mode of contraception; (2)participants with a clinically significant or unstable medical orsurgical condition that might preclude safe completion or might affectthe results. These include conditions causing significant CNS orautonomic dysfunction, including congestive heart failure, recent (<6months) myocardial infarct, cardiopulmonary disease, severe,uncontrolled hypertension, thrombocytopenia (<50×10⁹/L), severe anemia(<8 g/dL), immunocompromised state, liver or kidney disease(creatinine >2.3 mg/dL), uncontrolled diabetes mellitus (HbA1c>10 g %),alcoholism, malignant neoplasms, amyloidosis, uncontrolledhypothyroidism, sympathectomy, unstable peripheral neuropathies,concurrent infections, orthopedic problems that compromise mobility andactivity of daily living, cerebrovascular accidents, neurotoxin orneuroactive drug exposure, parkinsonism due to drugs (includingneuroleptics, alpha-methyldopa, reserpine, metoclopramide); (3)participants who have taken any investigational products within 60 daysprior to baseline; (4) Medications that could affect autonomic function.If patients are taking those medications, those are suspended prior toautonomic testing. Therapy with midodrine, anticholinergic, alpha andbeta adrenergic antagonists or other medications that affect autonomicfunction are withdrawn 48 hours prior to autonomic evaluations.Fludrocortisone doses up to 0.2 mg per day are permitted; (5) diseaseswith features of Parkinson's disease; e.g., diffuse Lewy body disease,progressive supranuclear palsy, essential tremor, hereditaryolivopontocerebellar atrophy, or postencephalitic parkinsonism; (6)dementia (DSM-IV criteria—Amer. Psych. Assoc., 1994). The score on theMini-Mental State Examination must be >24; (7) history ofelectroconvulsive therapy; (8) history of brain surgery for Parkinson'sdisease; (9) patients with contraindication for MRI scanning, includingthose with MRI-incompatible pacemakers; and (10) patients with activesystemic infection or local infection, which is close to the spinalinjection site.

Cells are isolated from adipose tissue. Briefly, a subcutaneous fatbiopsy is taken from either the abdomen or thigh of each human. Theactual site of the biopsy is determined by the general surgeon, at thetime of the procedure. The subject is given a local anesthetic (usually1% lidocaine) at the site of the biopsy. The fat biopsy is done througha small (1-2 inch) incision where approximately 15 cc of subcutaneousfat is removed from under the skin. The biopsy site is sutured with anintradermal absorbable suture that will not require suture removal. Thesuture is reabsorbed in 1-3 weeks.

The cells are expanded ex vivo and cryo-preserved during releasecriteria analysis. Cells are tested for phenotype, mycoplasma, culturesterility, and cytogenetic analysis. Cells not meeting release criteriaare not administered to the patient. In the event there is no cellgrowth from the tissue obtained from the first biopsy, one furtherattempt is carried out from a second biopsy. If the second attempt failsto grow cells, no further attempts are made.

After about 8 weeks, the autologous mesenchymal stem cells areadministered to each human via intrathecal injection. The autologousmesenchymal stem cells are placed in syringes at 4° C. and administeredwithin 12 hours. A lumbar spinal needle is placed in the subarachnoidspace, and a baseline CSF sample is collected. This baseline CSF sampleis analyzed for total nucleated cell count (with differential), totalCSF protein, glucose, IgG levels, immunoglobulin synthesis rate andindex, oligoclonal bands and cytology with emphasis on MSC markers. CSF(10 mL) is also retained for measurement of cytokines. The lumbarpuncture is performed into the lumbar subarachnoid space via a standardposterior, intervertebral approach between lumbar level 2 and 5. Theexact level is determined individually for each patient based onanatomical considerations. Next, mesenchymal stem cells are infused intothe CSF in 2-10 mL of Lactated Ringers solution over 1-2 minutes viafree-hand delivery, followed by a 1 mL flush with Lactated Ringers.After cell infusion and if the patient is tolerant, they are rotatedevery 15 minutes in a horizontal position (with help from nursing staffif necessary) for 2 hours to maximize even distribution of cells in theCSF.

The subjects are observed for any adverse events during and immediatelyfollowing the intrathecal injection. The patient's vital signs(including pain) are monitored every 15 minutes for one hour, and thenhourly for four hours, and then every four hours until discharge, whichis at least 48 hours after injection.

Escalating doses of mesenchymal stem cells are used across three patientgroups of 8 patients each (FIG. 1). Group 1 receives a single dose ofcells. Groups 2 and 3 receive two doses of cells separated by one month.The lowest dose of cells delivered is 1×10⁷. Group 1 patients areadministered a single intrathecal dose of 1×10⁷ cells. Group 2 patientsare administered one intrathecal dose of 5×10⁷ cells followed one month(±4 days) later by a second intrathecal dose of 5×10⁷ cells. Group 3patients are administered one intrathecal dose of 1×10⁸ cells followedone month (±4 days) later by a second intrathecal dose of 1×10⁸ cells.

All patients are followed on a regular basis for a minimum of 12 months(FIG. 2). Initial clinical follow-up is performed weekly with scheduledblood, CSF, and MRI evaluations for up to 8 weeks. Thereafter, patientsare subjected to clinical evaluations at six and twelve months. Phonefollow-ups are performed at three and nine months. Additionalevaluations take place if indicated by clinical status.

In some cases, the patients of Group 1, 2, or 3 receive a dose of 5×10⁷cells (±20%) once every 6 months (±1 month) for a total of fouradditional intrathecal injections. The autologous mesenchymal stem cellsare administered in 5 mL of Lactated Ringers solution over 1-2 minutes.

Example 5 Clinical Study to Evaluate Treating Multiple System Atrophy

Injection of all patients in groups 1 and 2 of Example 4 were completed.Each of these patients were followed for at least 8 weeks. Five patientscompleted one year of follow-up. In particular, 8 patients received asingle dose of 1×10⁷ cells, 8 patients received two doses of 5×10⁷cells, and 1 patient received two doses of 1×10⁸ cells.

The safety and tolerability experience was very positive. To this point,no serious adverse event attributable to the intrathecal injection ofautologous mesenchymal stem cells was observed. One patient experienceda temporary inguinal hernia incarceration four weeks after intrathecalinjection which required hospitalization for observation but resolvedspontaneously. This event was categorized as a severe adverse event, butwas determined to be definitely not related.

Asymptomatic imaging findings of focal nerve root thickening about thecauda equina in the area of intrathecal mesenchymal stem celladministration on scheduled MRI studies (7 weeks after first, 3 weeksafter second mesenchymal stem cell injection) were observed in fourpatients. All patients were and still are completely asymptomatic withunchanged neurological examination, and all four patients were in dosegroup 2. While this imaging finding was indeterminate, it was suspectedthat this phenomenon is an “implantation” response of mesenchymal stemcells. There was no suggestion of neural inflammation clinically norbased on CSF studies.

One patient presented imaging evidence of a subdural hematoma in thearea of repeated lumbar spinal taps. This was completely asymptomaticand was only discovered incidentally on scheduled MRI imaging. There wasno compromise of nerve roots or spinal cord, and a neurologic examremained unchanged.

Three patients noticed mild to moderate headaches following at least oneof the lumbar punctures, which were as expected of positional nature.All resolved spontaneously without intervention.

One patient in group 2 experienced fever 10 hours after the firstmesenchymal stem cell administration. The fever lasted approximately 30hours with a T_(max) of 38.9 degrees. There was no suggestion ofinfection. The fever resolved spontaneously without intervention. Theetiology remained indeterminate.

Two patients experienced urinary tract infections which is a commonoccurrence in multiple system atrophy related to bladder dysfunction,and not related to the administration of mesenchymal stem cells. Threepatients reported temporary low back or buttock discomfort. One patienthad temporary cramping of calf muscles, another patient noticedoccasional lower extremity muscle twitching, and another patient felt anincreased level of fatigue about one month after treatment. The etiologyof these events was uncertain, but unlikely to be directly related tothe administration of mesenchymal stem cells.

The following table summarizes adverse events by type, severity, andattribution seen in 19 patients (Table 1).

ADVERSE EVENT FREQUENCY SEVERITY ATTRIBUTION Asymptomatic MRI n = 4Mild- Definitely imaging findings Moderate Temporary n = 3 Mild-Possibly/ headaches Moderate Probably Low back n = 3 Mild- Possiblydiscomfort Moderate Muscle cramps/ n = 2 Mild Possibly/ twitchingProbably Not Urinary tract n = 2 Mild- Definitely Not infection ModerateFever n = 1 Moderate Possibly Fatigue n = 1 Mild Possibly Herniaincarceration n = 1 Moderate Definitely Not

The majority of patients who had late-follow up of 3 months or morereported a benefit from the treatment. The described benefit in thesepatients ranged from slowing of disease progression to notablefunctional improvement. In contrast, the natural history of multiplesystem atrophy was thoroughly studied, and the disease progressespredictably at a rate of 0.375 to 0.66 points per month on the firstpart of the Unified Multiple System Atrophy Rating Scale (UMSARS I, afunctional score of symptoms and ability to undertake activities ofdaily living). The placebo group, in a recently completed rifampicintreatment trial with patients enrolled at a similar disease stage as thepatients for this study and essentially identical inclusion/exclusioncriteria for selection, exhibited a rate of progression of 6 points overthe 48 weeks of the study (0.5 points per 4 weeks). The data from thisother study was used to generate a predicted progression slope(“historical controls”) and contrasted that to the progression observedin the patients who received intrathecal administrations of autologousmesenchymal stem cells (FIG. 3).

Only three patients progressed or were projected to progress at or abovethe rate predicted. The other 11 patients progressed or were projectedto progress less than predicted. In fact, several patients completed thestudy or were projected to complete the study with scores indicatingeither (a) lack of progression or (b) an improvement.

These results demonstrate that intrathecal administrations of autologousmesenchymal stem cells can be used to treat multiple system atrophy.

The twenty four patients completed one year of follow-up after receivingintrathecal mesenchymal stem cell injections. The safety and efficacydata remain highly favorable. The treatments were generally welltolerated with few adverse events. Changes on MRI imaging of the caudaequina (as described herein) were observed, and additional patientsreported temporary low back and leg pain following the treatments. Noattributable serious adverse events, however, were observed. On theother hand, efficacy data continued to be positive. Patients generallyprogressed at rates lower than expected, and some observed no diseaseprogression, while other observed improvement through the year followingtreatments. None of the patients experienced a rate of progression thatwas faster than the average of a historical control group (FIG. 5).

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method for slowing the progression of multiplesystem atrophy at a disease stage wherein a human has a Unified MultipleSystem Atrophy Rating Scale I (UMSARS I) score of 17 or less, whereinsaid method comprises: (a) determining that said human having multiplesystem atrophy has a UMSARS I score of 17 or less, (b) intrathecallyadministering, to said human, a composition comprising autologousmesenchymal stem cells, wherein said autologous mesenchymal stem cellsare adipose derived mesenchymal stem cells or bone marrow derivedmesenchymal stem cells, and (c) determining, at least three monthsfollowing said administering step, that said human has a UMSARS I scoreindicating no disease progression or improvement of said multiple systematrophy compared to said UMSARS I score of 17 or less.
 2. The method ofclaim 1, wherein said composition comprises from about 5×10⁶ to about5×10⁸ autologous mesenchymal stem cells.
 3. The method of claim 1,wherein said method comprises intrathecally administering saidcomposition comprising autologous mesenchymal stem cells more than onetime to said human.
 4. The method of claim 1, wherein said methodcomprises intrathecally administering said composition comprisingautologous mesenchymal stem cells to said human two to ten times.